Male hormonal contraception requires the administration of exogenous testosterone to suppress the pituitary gonadotropins FSH and LH. Current methods of testosterone delivery include intramuscular injections, implants, or a daily transdermal patch or gel, since oral administration of testosterone (in contrast to other steroids) was thought to be impractical. Nevertheless, we have recently shown that oral administration of testosterone (in the form of testosterone enanthate) results in normal levels of serum testosterone when coadministered with the 5-alpha-reductase inhibitor dutasteride. We believe that oral testosterone enanthate plus dutasteride might be a useful part of a male hormonal contraceptive regimen. However, no information exists about the ability of oral testosterone to suppress gonadotropin release and spermatogenesis in normal men[unreadable]the subject of this proposal. Specifically, our aims in this proposal are: 1) To determine the optimal dose of oral testosterone enanthate plus dutasteride to suppress gonadotropin secretion in men over a four week period. 2) To determine the best dose combination of oral testosterone/dutasteride and the oral progestogen medroxyprogesterone acetate to suppress gonadotropin secretion in men over an eight week period. 3) To determine the degree of spermatogenic suppression induced by combinations of oral testosterone, dutasteride and medroxyprogesterone acetate over a six month period. The experiments proposed in this submission will explore the ability of oral testosterone plus dutasteride combined with medroxyprogesterone to function as a hormonal contraceptive in man. Testosterone enanthate, dutasteride and medroxyprogesterone acetate are all commercially available and are safe for use in humans. These innovative studies will provide insight into the utility of oral testosterone and progestogens for male contraception, the physiology of gonadotropin suppression and the impact of oral testosterone administration on the maintainence of mood and sexual function in the setting of a male hormonal contraceptive regimen. In addition, this work might assist in the development of novel androgen therapies for men with testosterone deficiency. These studies will greatly inform efforts to create a usable, attractive reversible oral hormonal contraceptive for men, and help bring the dream of a "male pill" to fruition. PERFORMANCE SITE(S) (organization, city, state) University of Washington, Seattle, WA, USA PHS 398 (Rev. 04/06) Page 114 Form Page 2